Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by communication deficits and repetitive behavioral patterns. Hundreds of candidate genes have been implicated in ASD, including neurotransmission and synaptic (NS) genes; however, the genetic architecture of this disease...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-11-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/11/11/2971 |
| _version_ | 1797460054312484864 |
|---|---|
| author | Joana Vilela Hugo Martiniano Ana Rita Marques João Xavier Santos Muhammad Asif Célia Rasga Guiomar Oliveira Astrid Moura Vicente |
| author_facet | Joana Vilela Hugo Martiniano Ana Rita Marques João Xavier Santos Muhammad Asif Célia Rasga Guiomar Oliveira Astrid Moura Vicente |
| author_sort | Joana Vilela |
| collection | DOAJ |
| description | Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by communication deficits and repetitive behavioral patterns. Hundreds of candidate genes have been implicated in ASD, including neurotransmission and synaptic (NS) genes; however, the genetic architecture of this disease is far from clear. In this study, we seek to clarify the biological processes affected by NS gene variants identified in individuals with ASD and the global networks that link those processes together. For a curated list of 1216 NS candidate genes, identified in multiple databases and the literature, we searched for ultra-rare (UR) loss-of-function (LoF) variants in the whole-exome sequencing dataset from the Autism Sequencing Consortium (N = 3938 cases). Filtering for population frequency was carried out using gnomAD (N = 60,146 controls). NS genes with UR LoF variants were used to construct a network of protein–protein interactions, and the network’s biological communities were identified by applying the Leiden algorithm. We further explored the expression enrichment of network genes in specific brain regions. We identified 356 variants in 208 genes, with a preponderance of UR LoF variants in the <i>PDE11A</i> and <i>SYTL3</i> genes. Expression enrichment analysis highlighted several subcortical structures, particularly the basal ganglia. The interaction network defined seven network communities, clustering synaptic and neurotransmitter pathways with several ubiquitous processes that occur in multiple organs and systems. This approach also uncovered biological pathways that are not usually associated with ASD, such as brain cytochromes P450 and brain mitochondrial metabolism. Overall, the community analysis suggests that ASD involves the disruption of synaptic and neurotransmitter pathways but also ubiquitous, but less frequently implicated, biological processes. |
| first_indexed | 2024-03-09T17:00:00Z |
| format | Article |
| id | doaj.art-8492c3e91fe24c3fbc61a96560a41b2e |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T17:00:00Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-8492c3e91fe24c3fbc61a96560a41b2e2023-11-24T14:31:00ZengMDPI AGBiomedicines2227-90592023-11-011111297110.3390/biomedicines11112971Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection AnalysisJoana Vilela0Hugo Martiniano1Ana Rita Marques2João Xavier Santos3Muhammad Asif4Célia Rasga5Guiomar Oliveira6Astrid Moura Vicente7Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, PortugalDepartamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, PortugalDepartamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, PortugalDepartamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, PortugalDepartamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, PortugalDepartamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, PortugalUnidade de Neurodesenvolvimento e Autismo, Serviço do Centro de Desenvolvimento da Criança, Centro de Investigação e Formação Clínica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra (CHUC), 3000-602 Coimbra, PortugalDepartamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, PortugalAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by communication deficits and repetitive behavioral patterns. Hundreds of candidate genes have been implicated in ASD, including neurotransmission and synaptic (NS) genes; however, the genetic architecture of this disease is far from clear. In this study, we seek to clarify the biological processes affected by NS gene variants identified in individuals with ASD and the global networks that link those processes together. For a curated list of 1216 NS candidate genes, identified in multiple databases and the literature, we searched for ultra-rare (UR) loss-of-function (LoF) variants in the whole-exome sequencing dataset from the Autism Sequencing Consortium (N = 3938 cases). Filtering for population frequency was carried out using gnomAD (N = 60,146 controls). NS genes with UR LoF variants were used to construct a network of protein–protein interactions, and the network’s biological communities were identified by applying the Leiden algorithm. We further explored the expression enrichment of network genes in specific brain regions. We identified 356 variants in 208 genes, with a preponderance of UR LoF variants in the <i>PDE11A</i> and <i>SYTL3</i> genes. Expression enrichment analysis highlighted several subcortical structures, particularly the basal ganglia. The interaction network defined seven network communities, clustering synaptic and neurotransmitter pathways with several ubiquitous processes that occur in multiple organs and systems. This approach also uncovered biological pathways that are not usually associated with ASD, such as brain cytochromes P450 and brain mitochondrial metabolism. Overall, the community analysis suggests that ASD involves the disruption of synaptic and neurotransmitter pathways but also ubiquitous, but less frequently implicated, biological processes.https://www.mdpi.com/2227-9059/11/11/2971autism spectrum disorderultra-rare variantsprotein–protein interaction analysissynaptic and neurotransmitter genescommunity detection analysis |
| spellingShingle | Joana Vilela Hugo Martiniano Ana Rita Marques João Xavier Santos Muhammad Asif Célia Rasga Guiomar Oliveira Astrid Moura Vicente Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis Biomedicines autism spectrum disorder ultra-rare variants protein–protein interaction analysis synaptic and neurotransmitter genes community detection analysis |
| title | Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis |
| title_full | Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis |
| title_fullStr | Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis |
| title_full_unstemmed | Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis |
| title_short | Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis |
| title_sort | identification of neurotransmission and synaptic biological processes disrupted in autism spectrum disorder using interaction networks and community detection analysis |
| topic | autism spectrum disorder ultra-rare variants protein–protein interaction analysis synaptic and neurotransmitter genes community detection analysis |
| url | https://www.mdpi.com/2227-9059/11/11/2971 |
| work_keys_str_mv | AT joanavilela identificationofneurotransmissionandsynapticbiologicalprocessesdisruptedinautismspectrumdisorderusinginteractionnetworksandcommunitydetectionanalysis AT hugomartiniano identificationofneurotransmissionandsynapticbiologicalprocessesdisruptedinautismspectrumdisorderusinginteractionnetworksandcommunitydetectionanalysis AT anaritamarques identificationofneurotransmissionandsynapticbiologicalprocessesdisruptedinautismspectrumdisorderusinginteractionnetworksandcommunitydetectionanalysis AT joaoxaviersantos identificationofneurotransmissionandsynapticbiologicalprocessesdisruptedinautismspectrumdisorderusinginteractionnetworksandcommunitydetectionanalysis AT muhammadasif identificationofneurotransmissionandsynapticbiologicalprocessesdisruptedinautismspectrumdisorderusinginteractionnetworksandcommunitydetectionanalysis AT celiarasga identificationofneurotransmissionandsynapticbiologicalprocessesdisruptedinautismspectrumdisorderusinginteractionnetworksandcommunitydetectionanalysis AT guiomaroliveira identificationofneurotransmissionandsynapticbiologicalprocessesdisruptedinautismspectrumdisorderusinginteractionnetworksandcommunitydetectionanalysis AT astridmouravicente identificationofneurotransmissionandsynapticbiologicalprocessesdisruptedinautismspectrumdisorderusinginteractionnetworksandcommunitydetectionanalysis |